MicroRNA function in the nervous system Fiore, Roberto; Khudayberdiev, Sharof; Saba, Reuben ...
Progress in molecular biology and translational science,
2011, Letnik:
102
Journal Article
Recenzirano
MicroRNAs (miRNAs) are an extensive class of small noncoding RNAs that control posttranscriptional gene expression. miRNAs are highly expressed in neurons where they play key roles during neuronal ...differentiation, synaptogenesis, and plasticity. It is also becoming increasingly evident that miRNAs have a profound impact on higher cognitive functions and are involved in the etiology of several neurological diseases and disorders. In this chapter, we summarize our current knowledge of miRNA functions during neuronal development, physiology, and dysfunction.
The detection and subsequent quantification of photons emitted from living tissues, using highly sensitive charged-couple device (CCD) cameras, have enabled investigators to noninvasively examine the ...intricate dynamics of molecular reactions in wide assortment of experimental animals under basal and pathophysiological conditions. Nevertheless, extrapolation of this in vivo optical imaging technology to the study of the mammalian brain and related neurodegenerative conditions is still in its infancy. In this review, we introduce the reader to the emerging use of in vivo optical imaging in the study of neurodegenerative diseases. We highlight the current instrumentation that is available and reporter molecules (fluorescent and bioluminescent) that are commonly used. Moreover, we examine how in vivo optical imaging using transgenic reporter mice has provided new insights into Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Prion disease, and neuronal damage arising from excitotoxicity and inflammation. Furthermore, we also touch upon studies that have utilized these technologies for the development of therapeutic strategies for neurodegenerative conditions that afflict humans.
Prion diseases, also known as transmissible spongiform encephalopathies, are a group of neurodegenerative diseases that are invariably incurable. In fact, intense laboratory and clinical research ...have failed to discover effective treatments, to date, which delay the onset or progression of any neurodegenerative conditions, including those caused by infectious prions. It has become clear that profound changes in the brains of patients are evident long before clinical signs and it is at this stage that the disease is reversible and presents 'druggable' targets. However, research is beginning to uncover the molecular underpinnings involved in the early stages of disease pathogenesis. Targeting key genes and pathways using short non-coding RNA is a new avenue of exploratory research for the treatment of prion disease that holds much promise for the future.
This article reviews the novel approach of using RNA-based drugs as a therapeutic opportunity for prion disease. Furthermore, it discusses the challenges that currently exist in the development of these therapies and highlights the future opportunities in this area.
Numerous challenges exist before this therapeutic option can be translated into effective treatments. First, the crucial genes and pathways targeted must be identified from the multitude of temporally and spatially altered genetic processes that occur during the disease. Second, patients must be before irreversible neuronal degeneration, that accompanies prion replication, has progressed. Finally, these small RNAs must be delivered to the affected region of the brain over long periods of time and without significant side effects.
MicroRNAs (miRNAs) are important regulators of gene expression in virtually all eukaryotic cell types including the diverse cell types found in the CNS. They are involved in repressing gene ...expression by complementary hybridization to cognate protein-coding mRNAs. The likely involvement of miRNAs in disease processes requires both accurate detection and expression analysis strategies. In comparison to conventional methodologies to study miRNA expression, microar-rays offer an advantage in terms of throughput, sensitivity and specificity. Although microarrays are almost routinely used in laboratories for the analysis of mRNA, the small size of miRNAs presents challenges for their analysis in terms of probe design, target labeling and hybridization conditions. We discuss these issues in this chapter as well as highlighting the emerging perspectives in this field.
The ability to sense and respond to osmotic fluctuations is critical for the maintenance of cellular integrity. We used gene co-essentiality analysis to identify an unappreciated relationship between ...TSC22D2, WNK1, and NRBP1 in regulating cell volume homeostasis. All of these genes have paralogs and are functionally buffered for osmo-sensing and cell volume control. Within seconds of hyperosmotic stress, TSC22D, WNK, and NRBP family members physically associate into biomolecular condensates, a process that is dependent on intrinsically disordered regions (IDRs). A close examination of these protein families across metazoans revealed that TSC22D genes evolved alongside a domain in NRBPs that specifically binds to TSC22D proteins, which we have termed NbrT (NRBP binding region with TSC22D), and this co-evolution is accompanied by rapid IDR length expansion in WNK-family kinases. Our study reveals that TSC22D, WNK, and NRBP genes evolved in metazoans to co-regulate rapid cell volume changes in response to osmolarity.
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•TSC22D2, WNK1, and NRBP1 are functionally dominant gene family members•TSC22D, WNK, and NRBP protein families rapidly form reversible condensates•TSC22Ds mediate the translocation of NRBP1 into condensates•Association of TSC22Ds and NRBPs co-evolved with the expansion of IDRs in WNK kinases
Xiao et al. identify components of metazoan cell volume regulation machinery through gene co-essentiality analysis from large-scale CRISPR datasets. TSC22D, WNK, and NRBP genes sense rapid cell volume changes to form condensates, and disordered TSC22D proteins mediate the translocation of NRBP pseudokinases, which co-evolved in metazoans to regulate cell volume recovery.
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